Throughout this application, various publications, patents, and published patent applications are referred to by an identifying citation; full citations for these documents may be found at the end of the specification. The disclosure of the publications, patents, and published patent specifications referenced in this application are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.
The present invention relates to particulate products, hereinafter referred to as "advanced particulate media" or "particulate separation media" which have been carefully sized so as to permit the precise and selective separation of microparticles suspended in fluids, methods of using these media, the passing microparticulate suspensions obtained using these methods. The media and methods of the present invention are useful for generally reducing the quantity of coarse particulates (i.e., those with a particle size above a certain threshold) from a suspension while affording a means for selectively recovering finer particulates (i.e., those with a particle size below a certain threshold) suspended in a fluid. Unlike materials and methods used in general filtration (e.g., to remove particulates) and chromatography (e.g., to resolve particles), the advanced particulate media of the present invention, and their use, permit selective separation of microparticles according to particle size, in a manner analagous to a mechanical low pass filter.
The precise and selective separation of particles suspended in fluids according to particle size is a branch of the more general field of filtration. Filtration is a common means used to clarify fluids. Simple mechanical sieving and screening are often useful to provide filtration of coarse particulate matter, and numerous technologies using cyclones, hydrocyclones, and air classification have been employed to crudely separate particles in fluids. These types of filtration are often referred to as coarse filtration or particle filtration.
Ultrafiltration, which includes techniques such as crossflow filtration, gel permeation, and size exclusion chromatography are commonly used for analytical separations of macromolecules, colloidal suspensions, and ultrafine particulate matter which typically have particle sizes of less than 0.1 .mu.m.
Between particle filtration and ultrafiltration lies the region of microfiltration, for which the particulate matter to be separated is of a size range which usually results in visibly turbid fluids. Within the regions of microfiltration and particle filtration, the removal or separation of particulate matter roughly within the size range of 0.1 .mu.m to 500 .mu.m (i.e., microparticles) is usually accomplished on a small scale using membranes or papers constructed from natural, polymeric, or ceramic fibers. On larger commercial scale filtrations, or for increased filtration efficiency, particulate media such as diatomite are usually retained in a packed bed on a screen mesh or similar mechanical septum such as those used for coarse filtrations, thus offering superior convenience and economy for microfiltration.
The object of microfiltration, however, is usually to obtain clarity rather than selective particle separation within the microparticulate range. It is the typical goal of microfiltration to attempt to separate (or remove) all particulate matter from the fluid in which it is suspended, rather than perform a precise size separation of the particles suspended in a fluid and thereby leave certain particles suspended in the fluid.
Similarly, the advanced particulate media of the present invention and the methods of their use differ from the techniques used in size exclusion chromatography. The latter technique permits the resolution of particles according to size, that is, size exclusion chromatography provides the sequential separation of particles according to particle size. Like other chromatographic methods, size exclusion chromatography relies on the rate at which particles pass through the media to control the distribution of the particle sizes in the flowing stream, and thereby effect separation or resolution of very fine particles. To effect this resolution, size exclusion chromatography also requires uniformity of the particle size of the media. In sharp contrast, the advanced particulate media and the methods of using these media, as disclosed herein, effect separation of particles according to size with respect to a threshold. In this regard, the advanced particulate media of the present invention may conveniently be considered to be analogous to a mechanical low pass filter.
The working principles of filtration using particulate media have been developed over many years (Carman, 1937; Heertjes, 1949, 1966; Ruth, 1946; Sperry, 1916; Tiller, 1953, 1962, 1964), and have been recently reviewed in detail from both practical perspectives (Kiefer, 1991) as well as from their underlying theoretical principles (Bear, 1988; Norden, 1994). As a result, a number of methods to obtain optimum fluid clarity and process optimization have now been developed (e.g., Tarleton, 1994). A number of the theoretical principles of separating microparticulates have been discussed (Lloyd, 1975; Tianshou, 1988).
Particulate media are commonly used in three types of filtration techniques: (i) as stable but unconsolidated packed beds in depth filtration; (ii) as filter aids to pre-coat a septum and obtain spacing between microparticulates in the filter cake through continuous body feeding; and, (iii) as components of composites such as filter sheets, filter pads, or filter cartridges.
Depth filtration, in which a fluid is passed through a stable packed bed of unconsolidated media, is the most common method of water filtration. Rapid sand filtration and slow sand filtration are the most popular methods of filtration for municipal water facilities, which may use a variety of media in practice, for example, silica sand, silica gravel, anthracite, and garnet. Rapid sand and other types of depth filtration have historically been nonselective means of separation. The objective of this type of filter has been to remove microparticulate detritus, for example, algae, bacteria, and other kinds of microorganisms, while still allowing for high flow rates and low operating costs.
In the field of filtration, many methods of relatively nonselective particle separations from fluids involve the use of filter aids, that is, media intended to clarify the fluid from particulate matter. Examples of commonly used filter aids include diatomite and perlite, often preferred because of their high efficiency in practical filtration. Filter aids are often applied to a septum or support to improve clarity and increase flow rate in filtration processes, in a step sometimes referred to as "pre-coating." Filter aids are often added directly to a fluid as it is being clarified to lessen resistance to flow by reducing the load of undesirable particulate turbidity at the septum while maintaining a designed liquid flow rate, in a step often referred to as "body feeding." Depending on the particular clarification involved, filter aids may be used in pre-coating, body feeding, or both.
In some clarifying filtration applications, different filter aids are blended together to further modify or optimize the filtration process. In some cases, the combinations may involve simple mixtures of, for example, diatomite or perlite with cellulose, activated charcoal, clay, or other materials. In other cases, the combinations are composites in which filter aid products are intimately compounded with other ingredients to make sheets, pads, or cartridges. Still more elaborate modifications of these products are used for filtration, involving, for example, surface treatment or the addition of chemicals to filter aid products, mixtures, or their composites.
There are many cases in which the selective separation of particles is the desired outcome of a treatment process. In these situations, particles of two or more populations may be found together suspended in a fluid where removal of the coarser population and recovery of the finer population is highly desirable.
For example, there are many industrial microparticulate products, such as fillers and pigments, in which the utility and value of the product is enhanced if a product can be produced which contains few or no particles above a certain threshold diameter. For example, paint fillers with a specific particle size distribution are often used to adjust the texture of paint (e.g., high gloss, satin, or flat finish). Current industrial methods of obtaining such fillers, such as air cycloning, are often inadequate to provide fillers with optimum properties, such as particle size.
Another example in which the selective separation of particles according to size is desirable involves the specific separation of cell types in blood. Examples include the separation of white blood cells (i.e., leukocytes or leucocytes) from red blood cells (i.e., erythrocytes), and the separation of white blood cells from platelets, with the need to recover as many of the red blood cells or platelets, respectively, as possible.
The characteristics of these cellular components have been reviewed (Junqueira, 1975). Red blood cells are biconcave discs with an average maximum dimension of approximately 7.2 .mu.m, while platelets are cytoplasmic fragments having an average maximum dimension of approximately 5 .mu.m. While white blood cells are of several varieties, histology divides them into the larger granulocytes (e.g., neutrophils, basophils, eosinophils), which are spheroidal cells approximately 9 to 12 .mu.m in average maximum dimension, and the smaller agranulocytes (e.g., monocytes and lymphocytes), which are spheroidal cells approximately 6 to 12 .mu.m in average maximum dimension. Granulocytes undergo a process known as expansion when they contact solid surfaces, changing from a spheroidal shape to an amoeboid form, with the average maximum dimension increasing to approximately 22 .mu.m.
A number of methods to separate leukocytes from red blood cells and platelets have been developed, the most common methods being based upon filter elements composed of treated polymeric fibers (e.g., Pall, 1990a, 1990b, 1992a, 1992b, 1993a, 1993b, 1993c, 1994a, 1994b, 1994c, 1995a, 1995b; Pascale, 1994). A gel pre-filter and microaggregate filter are often suggested for use in combination with these in order to augment their performance. Often, extensive surface modifications to fibers are needed to obtain the desired separation properties (Marinaccio, 1990). In one instance, a fibrous glass filter has been used in conjunction with centrifugation to separate fibrin from serum (Adler, 1975). A study of the retention of platelets by glass bead filters was an example of filtration (Pitney, 1967), and platelet adhesion to glass beads has been examined in detail (Hellem, 1971) but, unlike the advanced particulate media of the present invention, the objective of these studies was not to obtain precise size selectivity.
Several methods for cell separation have been developed that rely on fluid mechanical principles of centrifugation rather than using porous media as means of separation (Goffe, 1993; Ishida, 1988, 1991, 1993; Powers, 1988; Hall, 1987; Kolobow, 1982, 1983; Latham, 1981a, 1981b; Columbus, 1977). Fetal red blood cells have been separated from maternal blood using centrifugation and gradient gels (Saunders, 1995; Teng, 1994, 1995), and by immobilized antibody binding (Calenoff, 1987). Agranulocytes have been separated from heavier blood components (Luderer, 1990, 1991; Terasaki, 1989), and other cell mixtures have been separated by attachment of organosilanized colloidal silica followed by density gradient centrifugation (Dorn, 1990a, 1990b).
Cells are reported to selectively bind to particles coated with antibodies, the coated particles having a relative density less than unity. These floating particles can then be concentrated, thus separating immunologically responsive cells, including white blood cell populations, from those which are not (Delaage, 1984, 1992, 1993). Granulocytes have been separated from agranulocytes by thixotropic gels (Smith, 1989, 1990) and related controlled buoyancy techniques (Carroll, 1987, 1989). Red blood cells have been chemically adsorbed to the surfaces of microspheres coated with antibodies, preferentially allowing leukocytes to remain in plasma while the microspheres are removed by magnetically induced agglutination (Kortwright, 1988). Other magnetic separations have also been described (e.g., Miltenyi, 1995a, 1995b; Yen, 1980; Vorpahl, 1994).
A method for separating certain lymphocytes from other leukocytes using porous particulate polymers in conjunction with animal serum proteins has been reported (Abe, 1984). An element for the analysis or transport of liquids, including biological fluids, created by joining polymeric particles with adhesive, has been described (Pierce, 1981). These methods rely on particulate polymers as a support to effect separation based on chemical affinity, rather than on selective discrimination of particle diameters as employed in the present invention.